Pharmacokinetics I

Drug administration and absorption

Prof. Hanan Hagar

Dr Ishfaq Bukhari
Pharmacology Department
By the end of this lecture, the student should be able to
 Know the meaning of pharmacology and its branches.

 Discuss the different routes of drug administration

 Identify the advantages and disadvantages of various routes

of drug administration
 Know the various mechanisms of drug absorption

 List different factors affecting drug absorption

 Define bioavailability and factors affecting it.

Recommended books

 Lippincott’s illustrated reviews

(Pharmacology) by Howland and Mycek

 Basic and Clinical Pharmacology by

Katzung
What is Pharmacology?

 From the Greek pharmakon (drug),

and legein (to speak or discuss)
 Broadly defined as the study of how
chemical agents affect living processes.
 e.g Hormones, Neurotransmitters and drugs
 What is Pharmacology
 Pharmacology studies the effects of drugs and
how they exert their effects.
 Acetylsalicylic acid (ASA) or Aspirin can reduce
 inflammation, , pain and fever
 It inhibit the action of a human cell membrane
enzyme known as cyclooxygenase
 Penicillin cures certain bacterial infections
disrupt the synthesis of cell walls in susceptible
 bacterial strains by inhibiting a key enzyme.
Pharmacology is the science that
deals with the drugs regarding
clasification, pharmacokinetics,
pharmacodynamics, side effects and
therapeutic uses.
Pharmacokinetics
are studies of the absorption, distribution,
metabolism & excretion of drugs.(ADME)
(what the body does to a drug?)

Pharmacodynamics
Are studies of
- Mechanisms of drug action.
- Pharmacological effects of drugs.
(what the drug does to the body?)
 Pharmacokinetics of drugs

Are studies of drugs regarding ADME

 Absorption
 Distribution
 Metabolism
 Excretion
 Drug
Excretion

Administration Metabolism

Blood
Absorption Site of action

Different organs &

Distribution tissues
 Enteral via gastrointestinal tract (GIT).
 Oral
 Sublingual
 Rectal
 Parenteral administration = injections.
 Topical application
 Inhalation
Advantages Disadvantages
- Common - Slow effect, GIT irritation
- Easy - Destruction by pH & enzymes
- Food - drug interactions
- Self use
- Drug-drug interactions
-convenient
- First pass effect
- cheap - No complete absorption
- No need for - Low bioavailability
sterilization
Not suitable for
vomiting & unconscious patient

 emergency & bad taste drugs

 First pass effect
 Drugs given orally are
first taken to the liver (via
portal circulation), where
they are metabolized
before reaching to the
blood to be distributed to
all other body
compartments.
Where does it occur?
 Liver
 GIT wall
 GIT lumen

First pass metabolism results in:

 Low bioavailability (low conc. of drug in blood).
 Short duration of action (t ½).
 drugs with high first pass effect should not be
given orally but parenterally.
Oral Dosage Forms (oral formulations)
 Tablets
 Coated tablets: sugar-coated to mask bad taste
 Enteric coated tablets: dissolve only in intestine
 Capsules
 Hard gelatin capsules: (contain powder)
 Soft gelatin capsules: (contain liquid)
 Syrup (e.g. Cough syrups)
 Suspension (mixture of solid in liquids e.g.
antibiotics).
Tablets Spansule

Hard- gelatin Soft- gelatin

capsule capsule
 Advantages Disadvantages
 Rapid effect not suitable
 can be used in emergency for
 High bioavailability Irritant drugs
 No first pass effect. Frequent use
 No GIT irritation

 No food drug – interaction

 Dosage form: friable tablet

(easily breaks and dissolves)

 Advantages Disadvantages
Suitable for
 children, vomiting,  Irritation of
unconscious patients rectal mucosa
 Irritant & bad taste drugs  Irregular

 less first pass metabolism

absorption &
(50%) bioavailability
Dosage form:

suppository or enema
 Intradermal (I.D.) (into skin)
Subcutaneous (S.C.) (under skin)
Intramuscular (I.M.) (into muscles)
Intravenous (I.V.) (into veins)
Intra-arterial (I.A.) (into arteries)
Intrathecal (I.T.) (cerebrospinal fluids )
Intraperitoneal (I.P.) (peritoneal cavity)
Intra - articular (Synovial fluids)
Advantages of injections
 No gastric irritation

 No food-drug interaction

 No drug-drug interaction

 No first pass metabolism

 higher availability than oral

Disadvantages
 Need skill

 Pain, tissue necrosis or abscess (I.M.)

 Anaphylactic reaction (I.V.)


 Intradermal administration
 Minute volume of drug (0.1 ml) not suitable
 suitable for vaccinations for large
 sensitivity test
volumes

Subcutaneous administration
 larger volume (0.1 ml – 1 ml) Not suitable
 used for sustained release effect for large
 suitable for poorly soluble
volumes
suspensions e.g. insulin zinc
preparation
 Intramuscular administration
 moderate volumes (3-5 ml) Not suitable for
 prolonged duration of  irritant drugs
action pain, abscess,

 oily preparations or poorly tissue necrosis may
soluble substances can be happen
used
 Intravenous administration
Advantages Disadvantages
 Large volume (500ml can be  used only for water
given by infusion) soluble drugs
 Rapid action (emergency)  Infection

 High bioavailability  Anaphylaxis

 No food-drug interaction  Sterilization

 No first pass metabolism  Expensive

 No gastric irritation
Not suitable
for oily solutions or
Suitable for poorly soluble
 Vomiting &unconscious substance
 Irritant & bad taste drugs.
Ampoule Vial
Single use Repeated use
Injection Advantages Disadvantages
I.D. minute volume (0.1 ml) not suitable for large volumes
suitable for vaccinations
& sensitivity test

S.C. Volume (0.1 ml – 1 ml ) not suitable for large volumes

suitable for poorly soluble
suspensions and for
instillation of slow-release
implants e.g. insulin zinc
preparation
I.M. Suitable for moderate not suitable for irritant drugs
volumes 3-5 ml, for oily Abscess- necrosis may happen
solutions or poorly soluble
substances

I.V. suitable for large volumes and not suitable for oily solutions
for irritating substances or poorly soluble substances
(500 ml can be given by Must inject solutions slowly as
infusion). a rule
 Drugs are mainly applied topically to produce
local effects. They are applied to
 Skin (percutaneous) e.g. allergy test, topical
antibacterial and steroids and local anesthetics.
 Mucous membrane of respiratory tract
(Inhalation) e.g. asthma
 Eye drops e.g. conjunctivitis
 Ear drops e.g. otitis externa
 Intranasal e.g. decongestant nasal spray
 Advantages Disadvantages
 rapid absorption
(due to large surface area) Not suitable for
 suitable for emergency irritant drugs
 provide local action

 limited systemic effect

Only few drugs
 less side effects
can be used
 no first pass effect

Dosage form:
 volatile gases e.g. anesthetics

 liquids given by aerosol,

nebulizer/inhaler for asthma
treatment
 are medicated adhesive patch applied to skin
to provide systemic effect (prolonged drug
action).
e.g. the nicotine patches (quit smoking).
e.g. Scopolamine (vestibular depressant,
antiemetic for motion sickness).
Nebulizer Atomizer
 Is the passage of drug from its site of
administration to site of action across cell
membranes.
Cell membrane

Sites of Sites of
Administration action
 Except for intravenous administration, all
routes of drug administration require that the
drug be absorbed from the site of
administration into the systemic circulation
(blood).
 I.V. administration requires no absorption
 Sites of Absorption & distribution Elimination
Administration
 The transport of drugs across cell membrane
occurs through one or more of the following
processes:
1. Simple diffusion = passive diffusion.
2. Active transport.
3. Facilitated diffusion.
4. Pinocytosis (Endocytosis).
 Aqueous diffusion: low molecular
weight and water soluble drugs can
diffuse through aqueous channels or
pores in cell membrane (filtration).
 Lipid diffusion: low molecular weight
and lipid soluble drugs are absorbed
via diffusion through lipid cell
membrane itself.
Characters
 Common.
 Occurs with or along concentration gradient.
 No energy
 No carrier
 Non selective
 Not saturable
 depends on lipid solubility.
 depends on pka of drug - pH of the
environment (it can be fluid of the cell body,
blood, urine).
 Most drugs are weak acids or weak bases.
 Drugs can exist in two forms ionized (water
soluble) & unionized forms (lipid soluble) in
equilibrium.
 Only unionized form is absorbable.
 Ionization of drugs reduce passage of drugs
across cell membranes.
The degree of ionization of drugs is determined
by their pKa and pH of the surrounding.
 Water soluble drugs = ionized = polar =
charged are difficult to permeate cell
membranes.

 Lipid soluble drugs = unionized = non

polar = uncharged are easy to permeate
cell membranes
 Affects degree of ionization of drugs.
 Weak acidic drugs  best absorbed in stomach
(in acidic medium of stomach, drug exists in
unionized form that is lipid soluble and easily
absorbed).

 Weak basic drugs  best absorbed in intestine.

(in basic medium of intestine, drug exists in
unionized form that is lipid soluble and easily
absorbed).
PKa of the drug
(Dissociation or ionization constant): pH at which
half of the substance is ionized & half is unionized.

 The lower the pKa value (pKa < 6) of the acidic

drug, the stronger the acid e.g aspirin
(Pka= 3.0).

 The higher the pKa value (pKa >8) of a basic

drug, the stronger the base e.g propranolol
( pKa= 9.4)
Which one of the following drugs will be best absorbed in
stomach (pH=1-2)?

Aspirin pka=3.0
Propranolol pka= 9.4
 relatively uncommon.
 occurs against concentration gradient.

 requires carrier and energy.

 specific or selective

 saturable

e.g.
 absorption of sugar, amino acids.

 uptake of levodopa by brain.

 Levodopa is used in treatment of parkinsonism

 occurs along concentration gradient
 No energy is required
 requires carriers
 selective
 Saturable
 Similar to entry of glucose into muscle.
Endocytosis:
uptake of membrane-bound particles.
Exocytosis:
expulsion of membrane-bound particles
Endocytosis occurs
for high molecular weight drugs
 large molecules such as peptides
 high polar substances, such as vitamin B12 & iron
 vitamin B12 combines with intrinsic factor.
 iron combines with transferrin.
OUT IN IN OUT
Factors affecting absorption :

 Route of administration.
 Dosage forms (depending on particle size and
disintegration, ease of dissolution).
(solution > suspension > capsule > tablet)
 Molecular weight of drug.
 Lipid solubility
 Degree of ionization
 Drug solubility (aqueous preparation better than
oily, suspension preparations)
 Chemical instability in gastric pH
(Penicillin & insulin )
 Factors affecting absorption :
 Surface area available for absorption.
 small intestine has large surface area than

stomach due to intestinal microvilli.

 Blood flow to absorptive site
 greater blood flow increases bioavailability

 Intestine has greater blood flow than stomach

 Intestinal motility (transit time)

 Diarrhea reduce absorption
 Gastric emptying
 drugs that increase gastric emptying
enhances absorption (metoclopramide).
 Drug interactions
 Food
 slow gastric emptying

 generally slow absorption

 Tetracycline, aspirin, penicillin V

 A fatty meal increase the absorption of

fat soluble antifungal drug (e.g. griseofulvin)

 Summary
 Different routes of administration are available
 Parenteral administration is the suitable route to
provide rapid effect.
 I.V. is used in emergency and provide high
availability
 Oral administration is best avoided during
emergency or when severe first pass metabolism
may occur
 Drugs may cross any cell membrane by simple
diffusion, active transport, facilitated diffusion,
and pinocytosis.
Active transport Carrier-mediated
facilitated diffusion
Against concentration along concentration
gradient gradient
(From low to high) (From high to low)
Needs carriers Needs carriers
saturable Saturable

Selective Selective
Energy is required No energy is required
Questions?